The primary function of the skin is to form a physical and chemical barrier between the external environment and the internal environment of the body, protecting the latter from harmful stimuli such as trauma, pathogenic agents or irritants, often through an inflammatory response. In fact, since inflammation helps to eliminate damaged cells so as to avoid further tissue damage, it is considered a protection mechanism against pathogenic organisms and other harmful agents.
The strength and duration of the inflammatory response depends on the context and type of stimulus; usually, the early stages of the inflammatory response form part of the so-called innate immune response.
In the skin, the production of ROS (Reactive Oxygen Species) free radicals at the skin level is a physiological mechanism which forms part of the normal cell metabolism, such as mitochondrial respiration. Moreover, the ROS free radicals can form after exposure to environmental stimuli and subsequent reactions of the immune system. ROS are normally neutralized by both enzymatic and non-enzymatic antioxidants, thereby keeping a balance between oxidant/antioxidant with tissue homeostasis.
However, excessive levels of ROS due to either a high production under stimulus or to an insufficient antioxidant activity lead to the so-called oxidative stress, with harmful effects through oxidative modification and functional and structural damage to biomolecules, such as lipids, proteins and DNA; or through dysregulation of cell signaling pathways, with triggering of downstream signaling cascades leading to the impaired release of cytokines, resulting in an exacerbation of inflammation.
Oxidative stress is a physiological condition in which there is an imbalance between the concentrations of reactive oxygen species (ROS) and antioxidants. An excessive accumulation of ROS leads, as said, to cellular damage, which can result in the development of many serious diseases: cancer, diabetes, cardiovascular diseases, atherosclerosis and neurodegenerative diseases. Under normal physiological conditions, the generation of cell ROS is counter-balanced by the action of cellular antioxidant enzymes and other redox molecules. Because of their potential harmful effects, excess ROS must be promptly eliminated from cells through antioxidant defense mechanisms. Compounds with antioxidant properties are therefore both hydrophilic and lipophilic molecules capable of metabolizing and eliminating the ROS.
In most cases, skin inflammation may initially be considered a protective process which develops to limit the damage from an injury or infection. However, the skin may also be subjected to excessive inflammatory responses resulting in the onset of chronic inflammation, auto-inflammation and autoimmunity. Acute inflammation of the skin can develop after the exposure to high doses of UV radiation (for example, sunburns), contact with allergens or chemical irritants. However, chronic inflammation of the skin is the result of a too sustained inflammatory response which ultimately seriously influences the skin health.
For example, in allergic contact dermatitis the relationship between ROS and inflammatory process was described by Esser et al., Contact Sensitizers Induces Skin Inflammation via ROS Production and Hyaluronic Acid Degradation, www.plosone.org, Volume 7|Issue 7|e41340, 2012. The data obtained identify an indirect mechanism of sensitization which induces the innate inflammatory response involving the degradation of the extracellular matrix ECM due to hyaluronic acid degradation by the ROS.
It is also known that skin inflammation leads to an alteration of the basic function of the skin barrier which, through a vicious circle, exacerbates the inflammatory condition itself and the ROS production. A defective cutaneous barrier permeability allows environmental allergens to penetrate the skin, resulting in the onset of immunological responses and of the inflammatory process.
In particular, the alteration of the barrier function is a central event in various skin alterations and diseases, such as sensitive skin, allergies (allergic and irritative dermatitis), eczema forms, atopic dermatitis, psoriasis.
Recent studies have shown that both environmental factors, such as UV radiation, and psychological stress are factors which can disrupt homeostasis and skin permeability.
In particular, published studies, such as Altemus et al., Stress-Induced Changes in Skin Barrier Function in Healthy Women, The Journal of Investigative Dermatology, Vol. 117, no. 2, 2001, or Denda et al., Stress alters cutaneous permeability barrier homeostasis, American Journal of Physiology, Vol. 278 no. 2, 2000, support the concept that psychological stress plays a determinant role in both the onset and in the severity of skin diseases such as psoriasis and atopic dermatitis.
EP0345362, owned by the same Applicant, describes active compounds, namely 2,4-monofurfurilidene-sorbitol and the relative tetra-ether 2,4-monofurfurilidene-1,3,5,6-O-tetra-alkyl-sorbitol, having an action of preventing the formation of endogenous and exogenous free radicals, and for this reason useful in cosmetic compositions for counteracting premature skin aging due to the action of the free radicals themselves. However, no anti-inflammatory activity is described for such compounds, nor are experimental data, which may be related to the skin barrier function or which may demonstrate other activities, reported.
It is the object of the present invention to propose compounds having antioxidant activity against ROS together with an anti-inflammatory activity, in particular capable of maintaining and restoring the barrier function of the skin, when compromised, suitable for pharmaceutical dermatological use or for cosmetic use for skin health and care.